Process of preparation of phosphinamides applications and new products

ABSTRACT

Phosphinamides are prepared by the action of an organic halide on an oxazaphospholidine. Depending upon the configuration desired for the stereoisomer to be obtained, an oxazaphospholidine is utilized which has been derived from a (+) or (-) optically-active amino-alcohol. These phosphinamides are useful for the preparation of phosphinates, in particular optically-active phosphinates of known absolute configuration; for this, the phosphinamide is subjected to alcoholysis.

This is a continuation-in-part of application Ser. No. 448,370, filedDec. 9, 1982, now abandoned.

The present invention relates to a new process for the production ofphosphinamides; it comprises certain phosphinamides as new chemicalproducts. The invention relates to the utilization of phosphinamides inthe preparation of various organic compounds of phosphorous, among whichthe phosphinates have a particular importance. A marked advantage of theinvention is that it makes possible the preparation of variousoptically-active compounds with good yields and with high opticalpurity.

The utility of phosphorus-containing organic compounds and in particularoptically-active compounds is well-known at present. It is known thatmany natural and synthetic products can now be prepared by asymmetricsynthesis, catalysed by means of transition metals and particularly bycatalysts comprising optically-active organo-phosphorus ligands.Substances of interest in agriculture, foodstuffs, pharmacy andperfumery are thus prepared. The production of L-DOPA, so useful intherapeutics, in particular for the treatment of Parkinson's disease, isan example. The development and study of these syntheses are limited atpresent by difficulty in preparing optically-active organo-phosphorusligands, which are very often employed in asymmetric catalysts.

The present invention relates to an improvement in this technique,rendering possible easier and more economical synthesis of a wholeseries of organo-phosphorus compounds, particularly phosphinamides and,from them, phosphinates, phosphine oxides, phosphines, phosphoniums,phosphinimides etc.

By starting with phosphinates, it is simple to obtain the variousproduce indicated above. It is thus important to be able to producephosphinates in a more economical manner than heretobefore. The methodsof the prior art are quite laborious; thus, that of Mislow, De Bruit etcoll. (Journ. Am. Chem. Soc. 91, 7393, 1969 and J. Org. Chem. 37,2272-1972) operate through the intermediary of methyl phosphinate,starting from a dichlorophosphine with division into two of thephosphinates, the whole of the process comprising 7 stages. Anothersynthesis route for optically-active phosphinates utilizes as thestarting material 1,3,2-oxazaphosphole (Tetrahedron Let. 571, 1980); italso necessitates division into two of the oxazaphospholes and the useof organo-metallic reagents, the whole of the operations comprising 4stages. In a general manner, the processes utilized at present give apoor final yield of phosphinates, they are lengthy, they necessitate amore or less difficult division into two of the intermediates andrequire the use of an industrially-obtainable key intermediate productwhich has two of the desired phosphinate substituents; in theseprocesses, the choice of the third substituent of the phosphinate isalso limited.

The new process according to the invention, which utilizes aphosphinamide by a reaction in a single stage, allows access to alldesired phosphinates by alcoholysis, which can be effected readily andunder economic conditions. The preparation of phosphinamides accordingto the invention may be effected very rapidly, namely in 15 minutes,with industrially acceptable yields; it may also be conducted moreslowly and give greater yields. About 1 hour generally suffices to passfrom the amide to the corresponding phosphinate. The intermediates ofthe process have good chemical stability; reagents or reactions whichare complex are not required, nor are severe operative conditions.Another substantial advantage, for the synthesis of optically-activeproducts, is the very elevated asymmetric induction.

The process according to the invention consists in preparing aphosphinamide by the action of an organic halide on oxazaphospholidine,and it is characterized in that it is carried out secure from air andhumidity, and preferably in the absence of light. This reaction can berepresented as follows: ##STR1## In the above formulae, the symbols R¹and R³ to R⁷ designate hydrocarbon groups or hydrogen atoms. Thesegroups are the same or different and, in particular can be aliphatic,cycloaliphatic and/or aryl. Preferably, when R³ and/or R⁶ arehydrocarbon groups, R⁴ and R⁵ represent hydrogen atoms. Among the R¹ andR³ to R⁷ substituents, the most common are C₁ to C₄ alkyls, phenyl andbenzyl; however, alkyls, for example C₁ to C₁₈, cyclopentyls,cyclohexyls, phenyls substituted by alkyls, naphthyls etc., can also bepresent. R² is an alkyl, aralkyl, cycloalkyl, aryl or saturated chaincarrying functions such as ester, ether, ketone, etc.

In a preferred embodiment of the invention, the reaction is carried outin obscurity. This is particularly desirable when the reagents aredissolved in a solvent.

According to one operative mode, the oxazaphospholidine A is taken inthe solid state and heated with a liquid alkyl, cycloalkyl or arylhalide, B; the phosphinamide C formed is crystallized from anappropriate solvent or separated in an oily form.

This new reaction, which provides the phosphinamide in a suitable yield,is particularly surprising as it has not previously been realized thatit could give such a result. In fact, authors who have attempted toapply it working in solution in toluene or some other solvent have onlybeen able to use it for polymers or have obtained badly-definednon-identifiable products (Arbuzov et coll. (Akad. Nauk. SSSP otd Kim.Nauk. 789, 1952)) or Mukaiyama et coll. (Bull. Chem. Soc. Jap. 40, 147,1967). In contrast therewith, good results are obtained according to theinvention, due to the absence of humidity and oxygen (and preferablylight) in the reaction zone of an oxazaphospholidine with an organichalide.

The reaction permits of preparing phosphinamide less or more rapidlywhen the temperature has a value of about 40° to about 100° C. When itis worked at lower temperatures, such as 10° to 40° C., and particularlyat ambient temperatures, especially between 15° and 30° C., the reactionis slower but yields and purities are higher.

Following a first embodiment of the invention, solid oxazaphospholidine(A) is heated to a desired temperature, within an inert gas atmosphere,in obscurity, secured from humidity; the appropriate organic halide (B),R² X, is added in excess to it and heating is continued during the timerequired. Yields of the order of 60% in phosphinamide may thus beobtained, and they are very good in comparison with those of knownmethods.

Following another embodiment of the invention, the oxazaphospholidineand the organic halide are first dissolved in an appropriate solvent,and the solution is kept at desired temperature, in an inert atmosphere,free from humidity, in obscurity, until a maximum of phosphinamide isformed.

Various conventional solvents are suitable, such for instance asaromatic, aliphatic, cycloaliphatic hydrocarbons or others. Particularlyuseful are mixtures of benzene hydrocarbons with cyclanes.

The starting material, oxazaphospholidine A, is a substance readilyobtainable in good yields by processes known in the art, particularly bythe action of a diamino-phosphine on an amino-alcohol. For example, bythe method described by Ternaki Mukaiyama and Yasuto Kodaira (Bull.Chem. Soc. Japan 39, (6), 1287-301 (1966)), 1,3,2-oxazaphospholidinesare obtained by the action of diamino-phosphine on an amino alcoholwhich, in the present case, can be ephedrine. The reaction can be showndiagrammatically in the following fashion: ##STR2## A diastereoisomer ofthis oxazaphospholidine can be given by the reaction indicated above, ifan optically-active amino-alcohol is used. An unexpected advantage ofthe invention lies in the fact that, starting from such anoxazaphospholidine by the action of the halide (B), a phosphinamide (C)is obtained with a very good preservation of the diastereoisometricpurity. Thus, starting with (-) ephedrine as the amino-alcohol, thisassists in the practical formation of a single one of the possiblediastereoisomers of oxazaphospholidine; the absolute configuration withrespect to the phosphorus atom is thus fixed.

As regards the possible transformations of the phosphinamides obtainedby the process of the invention, the most important is alcoholysis whichallows easy passage to the corresponding phosphinates according to thereaction: ##STR3## It can be seen that the process of the inventionallows selection as desired of the radicals R¹, R² and R⁸ for thedesired phosphinate E. In fact, R¹ is derived from the initialoxazaphospholidine A, R² is given by the halide, B, while R⁸ depends onthe choice of alcohol or phenol employed for the alcoholysis in thereaction (3).

A particular manner of carrying out the alcoholysis, according to theinvention, consists in catalysing the reaction with an ion exchangeresin; this brings about the advantage of facilitating the separation ofthe catalyst by mere filtration after alcoholysis.

The advantage indicated above of being able to prepare the phosphinamideC from an optically-active oxazaphospholidine A is reflected in theproduction of phosphinates according to the reaction (3). In fact,within the scope of the invention, it is possible to obtain phosphinatescorresponding to the two antipodes of the known absolute configuration,namely: ##STR4##

According to the conventions, by the above notation, R² is located abovethe page and R¹ below, while 0 and OR⁸ are in its plane. The antipodesof the absolute configuration R or S determining the phosphinate E canbe obtained respectively by the use of the (+) or (-) aminoalcohol inthe reaction (2) yielding the oxazaphospholidine. This result can alsobe obtained by introducing the groups R¹ and R² in a different order.The following Table of Formulae illustrates these possibilities.##STR5##

While the preparation of the oxazaphospholidines according to thereaction (2) is known as such and it is already known to effect thealcoholysis (3) of phosphinamides in order to convert them intophosphinates, the combination of the process of the invention (1) withthese two reactions forms a three-stage assembly of considerableinterest for obtaining phosphinates. Depending upon the nature of thecompounds utilized, the yield of each of these stages is about 60% to100% and the durations are about 12 hours for the reaction (2), 1/4 hourfor the conversion (1) and of the order of 1 hour for stage (3).

The non-limitative examples which follow illustrate the invention.

EXAMPLE 1

In view of the importance of oxazaphospholidines for the preparation ofphosphinamides according to the invention, the manner of operating toobtain one of these phospholidines, namely (+)3,4-dimethyl-2,5-diphenyl-1,3,2-oxazaphospholidine (2R, 4S, 5R), isdescribed below: ##STR6##

This is the compound A of the equation (1) given above in which R¹ andR⁴ are phenyls, R³ and R⁵ are hydrogen atoms, while R⁶ and R⁷ aremethyls. This is a new compound which has not previously been describedin technical literature.

The preparation is effected in a three-necked 1 liter flask providedwith an agitator and 2 nozzles for the introduction and removal of anitrogen sparge. In this way, the amine liberated during the reaction isseparated from the medium and can be measured in a washing flask.

0.1 mole of (-) ephedrine is reacted with 0.1 mole ofbis(diethylamino)-phenyl-phosphine for 12 hours in 500 ml of toluenebetween 100° and 110° C. under a light nitrogen stream.

After this time, the reaction mixture is transferred to an evaporationbottle and the volume of the solvent is adjusted to about 250 ml. Bysimple cooling under nitrogen, the product indicated above precipitates.After filtration and a new partial evaporation of the mother liquor,another fraction of the compound is also recovered.

The overall yield of the crystalline product is 70%; the product meltsat 100° C. and can be re-crystallized from toluene; it is stored in asealed receptacle in the refrigerator.

The NMR spectrum of the crude product of the reaction indicates a verygood chemical and diastereoisometric purity.

The following parameters were found:

    ______________________________________                                        NMR .sup.1 H (C.sub.6 D.sub.6)                                                            doublet   (3H)     0.5      ppm                                               "         "        2.4      ppm                                               multiplet (1H)     3.1      ppm                                               doublet   (1H)     5.4      ppm                                               multiplet (10H)    7.7-8    ppm                                   NMR (C.sub.6 D.sub.6) .sup.31 P                                                                              δ = +139.7                                                                       ppm                                   NMR (THF) .sup.31 P            δ = +141.6                                                                       ppm                                   ______________________________________                                        Analysis:                                                                              C %       H %    N %     O %  P %                                    ______________________________________                                        theory   70.84     6.69   5.16    5.90 11.42                                  found    70.69     6.66   5.27    5.65 11.50                                  Rotational Power: [α].sub.D.sup.22 = +40° ± 5° c =     2.3(C.sub.6 H.sub.6)                                                          ______________________________________                                    

EXAMPLE 2

Preparation of (-)3,4-dimethyl-2,5-diphenyl-2-oxo-1,3,2-oxazaphospholidine (2R, 4S, 5R)

3 g of the oxazaphospholidine (F) of Example 1 in solution in 50 ml oftoluene is left under agitation for 2 days in non-stoppered flask. Afterthis time, the toluene has evaporated and the residue is taken up onacetone. Diisopropyl ether is then added hot (about 50° C.), up to thelimit of solubility. The total volume of solvent must not be too large(about 20 ml). By cooling, the expected oxide precipitates. Therecrystallization solvent is also an acetone/diisopropyl ether mixture.

In the case of non-precipitation of the product, it is necessary tochromatograph the residue obtained by oxidation on a Merck No. 7734 typesilica column eluant 8/2 ether/acetone. The product leaves with an rf of0.7, which corresponds in general to about 10 100 ml fractions.

This preparation has been effected to verify the configuration of thecompound F; in fact, the oxo derivative ##STR7## has been described by DB Cooper et al, Tet. Lett. 2697 (1974) and as its absolute configurationis thus known; its production starting from compound F confirms theconfiguration proposed above for compound F. The melting point found is161° C.

By heating in air for 24 hours, an oxidized compound is obtained with ayield of 90%.

    ______________________________________                                        NMR .sup.1 H (CDCl.sub.3)                                                                  gives:                                                                        doublet    (3H)     0.91  ppm                                                 "          "        2.62  ppm                                                 multiplet  (1H)     3.76  ppm                                                 triplet    (1H)     5.76  ppm                                                 multiplet  (10H)    7.2-8.                                                                              ppm                                    NMR .sup.31 P (CDCl.sub.3)                                                                 δ = 33 ppm                                                 ______________________________________                                    

EXAMPLE 3

Preparation of (+) N-methyl-N-(1-methyl-2-iodo-2-phenyl)-ethyl(1S,2S)P-methyl-P-phenyl-phosphinamide (R).

The compound is obtained by the action of methyl iodide on thephospholidine F described in Example 1. ##STR8## The phosphinamide Gcorresponds to the formula C in which R², R⁶ and R⁷ are methyls, R¹ andR⁴ are phenyls and R³ and R⁵ are hydrogen atoms, the halogen X beingiodine.

The preparation is effected according to the following operative mode:0.1 mole of the oxazaphospholidine F in the solid state is heated for 10minutes at 95° to 100° under nitrogen, in a wide-mouthed filtrationtube. An excess (0.3 to 0.4 mole) of methyl iodide heated to the boilingpoint also under nitrogen is then rapidly added. The practicallyinstantaneous reaction is allowed to proceed for 5 to 10 minutes. Bycooling, the expected product crystallizes, provided there is not toomuch iodide in excess. However, the latter is eliminated easily byevaporation. The residue, whether or not it is crystallized is taken upin hot acetone and taken to the limit of solubility by diisopropyl ether(total volume of solvent 200 ml). By cooling, the desired productprecipitates; yield 60%.

The melting point of the product obtained is 160° to 162° C.

    ______________________________________                                        NMR .sup.1 H (CDCl.sub.3):                                                                  doublet   (3H)     1.1    ppm                                                 "         "        1.95   ppm                                                 "         "        2.45   ppm                                                 multiplet (1H)     4.30   ppm                                                 doublet   "        5.15   ppm                                                 multiplet (10H)    7.1-8.20                                                                             ppm                                   ______________________________________                                        Elementary Analysis:                                                                   C %    H %      N %  O %    P %  I %                                 ______________________________________                                        theory   49.41  5.20     3.39 3.87   7.50 30.70                               found    49.63  5.29     3.35 3.87   7.54 30.57                               [α].sub.D.sup.21 = +162.5°                                                           c = 2.5(CH.sub.3 OH)                                      NMR .sup.31 P (CDCl.sub.3) δ = +35.1 ppm                                ______________________________________                                    

EXAMPLE 4

Preparation of (+)N-methyl-N-(1-methyl-2-iodo-2-phenyl)-ethyl(1S,2S)P-methyl-P-phenyl-phosphinamide(R).

This is an analogue of the phosphinamide G of Example 3 in which themethyl on the phosphorus atom is replaced by an ethyl. This compound isprepared from the phospholidine F of Example 1 by an operation similarto that of Example 3, the methyl oidide being replaced by ethyl iodide.Heating under reflux at 70° takes place for 8 minutes.

The crude product of the reaction, after evaporation of the halide, issubjected to chromatography on alumina with ethyl acetate as the eluant.The expected phosphinamide is recovered after ten 100 ml fractions. Theproduct has the form of a thick oil. Its configuration is the same, thatis to say (R)_(p), as that of the compound G described in Example 3.

    ______________________________________                                        NMR .sup.1 H (CDCl.sub.3) examination indicates:                              ______________________________________                                        doublet       (3H)        1.1 ppm                                             triplet       "           1.25 ppm                                            "             "           2.40 ppm                                            multiplet     (2H)        2.10 ppm                                            "             (1H)        4.20 ppm                                            doublet       (1H)        5.25 ppm                                            multiplet     (10H)       7.2-8.25 ppm                                        ______________________________________                                        Micro-analysis:                                                                            C %         H %    N %                                           ______________________________________                                        calculated   50.60       5.43   3.28                                          found        50.48       5.54   3.24                                          [α].sub.D.sup.21 = +116°                                                             c = (CHCl.sub.3).                                         ______________________________________                                    

EXAMPLE 5

Preparation of (+)N-methyl-N-(1-methyl-2-bromo-2-phenyl)-ethyl(1S,2S)P-benzyl-P-phenyl-phosphinamide(R).

The desired product is a phosphinamide analogous to that of formula C ofreaction (1); it is a substance in which R¹ is a phenyl, R² is a benzyl,R³ is a hydrogen atom, R⁴ is a phenyl, X is a bromine atom, R⁵ is ahydrogen atom and R⁶ and R⁷ are methyls.

The preparation consists of heating 0.1 mole of the oxazaphospholidine Fof Example 1 at 90° C. under nitrogen and rapidly adding 8 moles ofbenzyl bromide maintained at the same temperature, also under nitrogen.The reaction is allowed to proceed for 10 minutes.

After cooling and evaporation under vacuum of the excess benzyl bromide,the residue is taken up in hot acetone. On cooling, crystals of amixture of the diastereoisomers of the phosphinamide formed aredeposited. With this halide in fact and under the operative conditionsindicated above, some degree of epimerisation around the phosphorusatoms is confirmed.

After filtration and evaporation of the acetone, the residue ischromatographed on basic alumina at the rate of 3 g per 100 g of Al₂ O₃.The phosphinamide leaves after 10 50 ml fractions and the NMR analysisrevealed a correct diastereoisometric purity. For the more abundantdiastereoisomer of the configuration (R)_(p), this gives the followingindications:

    ______________________________________                                        NMR .sup.1 H (CDCl.sub.3)                                                                    doublet   (3H)     1.05 ppm                                                   "         "        2.50 ppm                                                   multiplet (2H)     3.65 ppm                                                   "         (1H)     4.30 ppm                                                   doublet   (1H)     5.05 ppm                                                   multiplet (15H)    7-8.2 ppm                                   ______________________________________                                    

The mixture of diastereoisomers isolated by crystallization has amelting temperature of 180°-183° C.

    ______________________________________                                        NMR .sup.1 H(CDCl.sub.3)                                                      doublet (3H) doublet (3H) triplet (3H) multiplet (1H) multiplet                            0.65 ppm 1.05 ppm 2.55 ppm 3.65 ppm 4.30 ppm                                             ##STR9##                                              otherwise doublet (1H) doublet (1H)                                                         5.05 ppm 4.85 ppm                                                                       ##STR10##                                             Analysis:                                                                              C %    H %      Br % N %    O %  P %                                 ______________________________________                                        calculated:                                                                            62.45  5.70     18.06                                                                              3.17   3.62 7.00                                found:   62.81  5.80     17.94                                                                              2.83   3.76 7.01                                ______________________________________                                         [α].sub.D.sup.21 =                                                      c = 1.2(CHCl.sub.3)                                                      

EXAMPLE 6

A phosphinamide analogous to that of Example 5, but having a chlorineatom in place of the bromine atom, is prepared.

The preparation takes place as in the foregoing case, but with benzylchloride which gives a diastereoisometric purity of 80/20.Crystallization of the mixture of diastereoisomers from acetoneeliminates the major part of the epimer.

After evaporation of the solvent, the residue obtained is subjected tochromatography on basic alumina (3 g per 100 g of alumina; eluent:ethylacetate). The diastereoisomer leaves after 10 50 ml fractions. The maindiastereoisomer prepared, of the configuration (R)_(p), has a meltingpoint of 154° to 157° C.

    ______________________________________                                        The NMR (CDCl.sub.3) gives:                                                   ______________________________________                                        doublet        (3H)        1.05 ppm                                           "              "           2.50 ppm                                           multiplet      (2H)        3.60 ppm                                           "              (1H)        4.30 ppm                                           doublet        "           4.95 ppm                                           multiplet      (15H)       7.20-8.00 ppm                                      ______________________________________                                        [α].sub.D.sup.21 = +130° c = CHCl.sub.3 NMR                      .sup.31 P(CDCl.sub.3) δ = +36.34 ppm                                    Analysis:                                                                              C %    H %      Cl %  N %    O %  P %                                ______________________________________                                        calculated                                                                             69.42  6.33     8.91  3.52   4.02 7.78                               found    68.55  6.43     8.69  3.43   4.54 7.17                               ______________________________________                                    

The mixture of diastereoisomers isolated by crystallization (R)_(p)+(S)_(p), has a melting point of 175° C. Its NMR (CDCl₃) indicates:

    ______________________________________                                        doublet       (3H)        0.55 ppm                                            "             "           1.00 ppm                                            triplet       (2H)        2.0 ppm                                             multiplet     "           3.50 ppm                                            "             (1H)        4.20 ppm                                            doublet       "           4.80 ppm                                            "             "           4.95 ppm                                            multiplet     (15H)       7.00-8.20 ppm                                       [α].sub.D = +123°                                                          c = 1.2 CHCl.sub.3                                                                        NMR .sup.31 P(CDCl.sub.3) α = +36.47                                    and +36.21 ppm.                                         ______________________________________                                    

EXAMPLE 7

Application of the phosphinamide of Example 3 (G) to the preparation ofmethyl methyl-phenyl-phosphinate of the configuration R(+).

290 mg of the phosphinamide are dissolved in 1.76 N methanolic hydrogenchloride solution. After an hour, 10 ml of a 2.8 N methanolic ammoniasolution is added to neutralize the acid. After evaporating the solventand taking up the residue in 10 ml of methylene chloride, this isfiltred to eliminate mineral salts. A new evaporation of the solventgives a residue which is subjected to chromatography on silica withacetone as the eluant (20×20 plates). After extracting with methanol,the band between rf 0.55 and 0.65, the phosphinate formed is recovered.

[α]=52°

c=3 (benzene, which represents 93% optical purity).

NMR examination has confirmed the structure of this phosphinate knownfrom prior literature (M. J. P. Harguer, Journ. Chem. Soc. Perkin I,1294 (1979)).

EXAMPLE 8

Application of the phosphinamide of Example 4 for the preparation ofmethyl methyl-phenyl-phosphinate of the configuration R(+).

500 mg of the phosphinamide are dissolved in 50 ml and 0.15 M methanolicsolution of methane-sulphonic acid and the solution is allowed to standfor 1/2 hour at 60° C. After this time, it is neutralized with 100 ml ofa 4M ammonical solution. After evaporation of the solvent, the residueis taken up in 30 ml of methylene chloride and the insoluble mineralsalts are separated by filtration. After a new evaporation, the residueis chromatograped on silica with acetone as eluant. The phosphinateformed is recovered after the elution of 10 fractions of about 50 ml.This product, known in the art, is oily and has an [α]_(D) =+22.7°, c=7(methanol); optical purity=47%. The NMR confirms the structure indicatedabove.

EXAMPLE 9

Application of the phosphinamide of Example 6 to the preparation ofmethyl R(-) benzylphenyl-phosphinate.

2.2 g of the phosphinamide is dissolved in 50 ml of an 0.1M methanolicsolution of methane-sulphonic acid and the solution is maintained at 55°C. for 2 hours. After neutralization with a 1M methanolic ammoniasolution, the solvent is driven off. On taking up in methylene chloride,the residue is filtered and the solvent again evaporated. A filtrationon 50 g of alumina for 2 grams gives the phosphinate after severalfractions, the eluant being ethyl acetate.

The melting point of the racemate is 96° C. The optically-activephosphinate has a [α]_(D) =-3.2° for c=6 (methanol), at 77% opticalpurity.

    ______________________________________                                        The NR (CDCl.sub.3) gives:                                                                    doublet   (2H)    3.3 ppm                                                     "         (3H)    3.6 ppm                                                     multiplet (H)     7-7.8 ppm                                   ______________________________________                                    

There is therefore a new phosphinate obtained according to the inventionwhich has not been known before. Starting from phosphinates derived fromthe phosphinamides obtained according to the invention, a whole seriesof phosphine oxides have been prepared by the method of Mislow et coll.(Journ. Am. Chem. Soc., 90, 4842 (1968)), particularly:

benzyl methylphenyl-phosphine oxide R(+)

benzyl methylphenyl-phosphine oxide S(-)

ethyl methylphenyl-phosphine oxide R(+)

ethyl methylphenyl-phosphine oxide S(-)

methyl o-methoxy-phenylphenyl-phosphine oxide R(+)

methyl phenyl-β-mapthyl-phosphine oxide R(+)

It will be noted that the oxazaphospholidine (F) prepared according toExample 1, all the phosphinamides of Examples 3 to 7 as well as themethyl benzylphenyl-phosphinate of Example 9 and in particular theiroptically-active isomers are new chemical products.

EXAMPLE 10

Preparation of (+)N-methyl-N-(1-methyl-2-iodo-2-phenyl)-ethyl(1S,2S)phosphonamide R insolution in toluene.

This compound is obtained by the action of methyl iodide on theoxazaphospholidine F of Example 1.

In a 3-neck 1-liter flask, 0.1 mole of oxazaphospholidine F is dissolvedin 500 ml of toluene; 0.5 mole of methyl iodide is then added underagitation. The mixture is heated under nitrogen at 80° C. for 1 hour.After standing, a clear yellow oil separates; the toluene is evaporatedand also the excess methyl iodide. The oil obtained by evaporation ofthe toluene is subjected to chromatography on basic alumina with ethylacetate as the eluant. The phosphinamide is recovered after 10 150 mlfractions. The pure product has a crystalline form, the NMRcharacteristics of which are identical to those of the product ofExample 3, but the yield of crystalline product is only about 7% asagainst 60% in Example 3, where the preparation has been effectedwithout a solvent.

This example thus shows that prolonged heating at 80° C. in light leadsto a bad yield in phosphinamide. The yield exceeds 60% when operation iscarried out in obscurity, under nitrogen, without humidity, during 12minutes only.

EXAMPLE 11

Preparation of aP-methyl-P-phenyl-N-methyl-N-(1-methyl-2-bromo-2-phenyl)-ethylphosphonamide.

The preparation of this phosphinamide differs from that of Example 3because methyl bromide is gaseous and it is not possible to react iteasily with solid oxazaphospholidine.

The following operative mode is utilized.

Gaseous methyl bromide is added to 500 ml of a toluene solution of theoxazaphospholidine F of Example 1, by bubbling it in excess through thesolution maintained at 80° C. for half an hour. The solvent and also theexcess methyl bromide are then eliminated. The oil obtained byevaporation of the toluene is subjected to chromatography on aluminawith ethyl acetate as the eluant. The yield of the reaction is lowerthan 5%, which confirms the conclusion of Example 10.

The phosphinamide is recovered after 10 100 ml fractions of solvent. Ithas the form of an oil, the NMR examination of which indicates:

    ______________________________________                                        doublet        (3H)        1.1 ppm                                            "              "           1.9 ppm                                            "              "           2.4 ppm                                            multiplet      (1H)        4.5 ppm                                            doublet        "           5 ppm                                              "              (10H)       7.2-8 ppm                                          ______________________________________                                    

This compound is new.

EXAMPLE 12

Preparation of (-) 3,4-dimethyl 2,5-diphenyl 1,3,2-oxazaphospholidine(2S,4R,5S) i.e. an antipode compound of the one (F) described in Example1.

Therefore the operations of Example 1 are exactly repeated but startingfrom (+) ephedrine instead of (-) ephedrine.

The product thus obtained has a very good chemical and diasteroisomericpurity. Its melting point of 100° C. (recrystallization in toluene) andits NMR characteristics are the same as those of the above mentionedproduct F, shown in Example 1, while its [α]_(D) ²⁰° is -40°±5 (c=2.5 C₆H₆) instead of +40%±5 for the compound F.

Now the new (-) oxazaphospholidine involved has the configuration:##STR11##

EXAMPLE 13

Preparation of (+) N-methyl N-(1-methyl 2-iodo 2-phenyl)-ethyl (1S,2S)P-methyl P-phenyl phosphinamide (R) within a solvent without heating.

Starting reagents are here the same as in Example 3, but they aredissolved in a mixture of equal volumes of benzene and cyclohexane. Thus0.01 mol of oxazaphospholidine (F of Example 1) is dissolved in 80 ml ofthat mixture in a flask having a 250 ml capacity; then 0.035 mol of CH₃I, previously filtered on basic alumina, is added thereto. The inside ofthe flask is cleaned with a nitrogen stream and with this inertatmosphere it is tightly stopped, and then left for 72 hours inobscurity at room temperature. After this time, a partially crystallizedoil settled at the bottom of the flask.

Now, the solvent is evaporated and the product subjected to NMR analysiswhich shows a yield of 84% in phosphinamide. By recrystallization inacetone, a pure product, identical to the G compound of Example 3 isobtained.

Comparison with Examples 10 and 11 thus shows a considerable improvementdue to working in obscurity, without humidity at room temperature.

EXAMPLE 14

Preparing (-) N-methyl N-(1-methyl-2-iodo 2-phenyl)-ethyl (1R,2R)P-methyl P-phenyl phosphonamide (S).

This compound is the antipode of the (R) phosphinamide designated by Gin Example 3. It is prepared from the (-) oxazaphospholidine of Example12, the preparation of which has been started from (+) ephedrine.

Now, the above (S) phosphinamide is prepared in the same manner asexposed in Example 13, within the same solvent mixture of aromatichydrocarbon and cyclane; the same yield is obtained and the samecharacteristics as those of the G compound, except that rotary power[α]_(D) ²¹ is -162.5° (c=2.5 CH₃ OH) instead of +162.5°.

EXAMPLE 15

Preparation of (+) N-methyl N(1-methyl 2-bromo 2-phenyl)-ethyl (1S,2S)P-benzyl P-phenyl phosphonamide (R).

The same product is concerned as in Example 5, but the preparation iscarried out in homogenous medium, cold, the reagents being previouslydissolved in a mixture of 1:1 benzene/cyclohexane.

0.01 mol oxazaphospholidine (F) and 0.03 mol purified CH₂ Br are used asa solution in 80 ml of the solvent mixture. After 7 days at roomtemperature, in nitrogen atmosphere, secure from light and humidity, 3.5g of diastereoisomer crystals are recovered, which represents a yield of60.3% in phosphinamide (R) with respect to the startingoxazaphospholidine.

EXAMPLE 16

Application of the phosphinamide G of Example 3 to the preparation ofcorresponding methyl phosphinate.

The preparation is similar to that of Example 7, except that it iscarried out by contacting the reaction medium with an ion exchange resinas catalyst.

To 0.413 g (0.001 mol) of phosphinamide dissolved in 50 ml of methanol,1 g of acid ion exchange resin DOWEX 50W is added, the resin having beenpreviously washed with aqueous 10% HCl, then with water, further withmethanol and dried. After 1 hour stirring at ambient temperature, themixture is filtered and the methanol is evaporated.

The residue thus obtained is subjected to chromatography on silica withacetone as eluant; it is constituted by a methyl phosphonate having[α]_(D) ²⁰ =+47° (c=2 C₆ H₆) and an optical purity of 82%.

The new catalyst used, the ion exchanger, bears the advantage of beingeasily separable by mere filtration.

EXAMPLE 17

A transformation into methyl phosphinate, in a manner identical withthat of Example 16, has been carried out on the phosphinamide (R)obtained according to Example 13. Thus, methyl methyl-phenyl-phosphinateof configuration S(-) has been obtained instead of that having theconfiguration R(+) as in Examples 7 and 13.

This compound has [α]_(D) ²⁰ =-45° (c=2 C₆ H₆) its optical purity being78%.

EXAMPLE 18

Examples 3, 10 and 13 were repeated in order to show the influence oflight, air and humidity on the reaction to produce phosphinamides by theprocess of this invention. Where purified organic halide is mentioned,this means that the halide was first filtered through active alumina(activated at 140° C. for 24 hours) so that no humidity remained in thehalide. The tables below give the yield percent in phosphinamide withrespect to the oxazaphospholidine used in each run.

Repetition of Example 3:

Working with solid oxazaphospholidine preheated to 110° and then reactedwith CH₃ I for 10 minutes:

    ______________________________________                                        Example   Purified Under      Day   Yield                                     No.       Halide   Nitrogen   Light %                                         ______________________________________                                        3         no       yes        yes   60                                        3a        yes      yes        yes   75                                        3b        no       no         yes   15                                        3c        yes      no         yes   30                                        3d        yes      yes        no    80                                        ______________________________________                                    

These results show that when working under light, it has been possibleto reach a yield of 75% where there is neither humidity or oxygen.Humidity alone, although detrimental, permits a yield of 60%. Oxygenalone causes a strong drop to 30%. When humidity and air are bothpresent, the result is very bad. Repeating experiment 3a in the absenceof light gave a yield of 80%, which shows that considerable technicalprogress has been achieved.

Repetition of Example 10:

A solution of oxazaphospholidine in toluene at 80° C. is mixed with CH₃I and kept at 80° C. for one hour:

    ______________________________________                                        Example   Purified Under      Day   Yield                                     No.       Halide   Nitrogen   Light %                                         ______________________________________                                        10        no       yes        yes   7                                         10a       yes      yes        yes   20                                        10b       yes      no         yes   0                                         10c       no       no         yes   0                                         10d       yes      yes        no    24                                        ______________________________________                                    

Repetition of Example 13:

Oxazaphospholidine dissolved in a mixture of benzene and cyclohexane wasreacted with CH₃ I at room temperature for 72 hours:

    ______________________________________                                        Example   Purified Under      Day   Yield                                     No.       Halide   Nitrogen   Light %                                         ______________________________________                                        13        yes      yes        no    84                                        13a       yes      yes        yes   60                                        13b       no       yes        yes   55                                        13c       yes      no         yes   10                                        13d       no       no         yes    0                                        ______________________________________                                    

The foregoing results show that while light does not have as strong aninfluence as humidity and air, working in the absence of light permitsobtaining a high increase in yield (84% v. 60%).

What is claimed is:
 1. Process for the preparation of a phosphinamide,characterized in that an organic halide is reacted with anoxazaphospholidine in the absence of air and of humidity and in whichthe reaction is carried out in the absence of light.
 2. Processaccording to claim 1, characterized in that the preparation is carriedout according to the reaction: ##STR12## where the symbols R¹ and R³ toR⁷ designate hydrogen atoms or the same or different aliphatic,cycloaliphatic or aryl hydrocarbon groups, X is chlorine, bromine oriodine, R² in an alkyl, aralkyl, aryl, cycloalkyl or a saturated chaincarrying ester, ether or ketone functional groups.
 3. Process accordingto claim 2, characterized in that the alkyls are C₁ to C₁₈.
 4. Processaccording to claim 3 in which the alkyls are C₁ to C₄.
 5. Processaccording to claim 2 or 3, characterized in that at least one of R¹ andR³ to R⁷ represents phenyl, substituted phenyl, benzyl, napthyl,cyclopentyl or cyclohexyl.
 6. Process according to claim 2,characterized in that the oxazaphospholidine, in the solid state, isheated with an excess of the organic halide.
 7. Process according toclaim 1, characterized in that the preparation takes place at atemperature of 10° to 100° C.
 8. Process according to claim 7, whereinthe temperature is 10° to 40° C.
 9. Process according to claim 7,wherein the oxazaphospholidine and the organic halide are dissolved inan organic solvent.
 10. Process according to claim 9, in which thesolvent is a mixture of aromatic hydrocarbon and a cyclane.
 11. Processaccording to claim 1, for the preparation of optically-activephosphinamides, characterized in that, depending upon the configurationdesired for the stereoisomer to be obtained, a (+) or (-)oxazaphospholidine is used.
 12. Process according to claim 11,characterized in that the antipodean stereoisomers of known absoluteconfiguration are prepared from one or other of the two types ofoxazaphospholidine, by utilizing an organic halide R² X with anoxazaphospholidine carrying a group R¹ on the phosphorus or a halide R¹X with an oxazaphospholidine the P of which carries a group R², the twosubstituents R¹ and R² being different one from the other, R¹representing hydrogen or an aliphatic, cycloaliphatic or arylhydrocarbon group and R² representing an alkyl, aralkyl, aryl orcycloalkyl or saturated chain carrying ester, ether or ketone functionalgroups.
 13. Process according to claim 2, wherein the product obtainedis further heated with an alcohol with the addition of an alcoholysiscatalyst to produce a phosphinate.
 14. Process according to claim 13, inwhich the catalyst is an ion exchange resin.